Atlas of Genetics and Cytogenetics in Oncology and Haematology
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))
| Identity |
| Other names | MDC9 |
| Meltrin-gamma | |
| MLTNG | |
| MCMP | |
| KIAA0021 | |
| HGNC (Hugo) | ADAM9 |
| LocusID (NCBI) | 8754 |
| Location | 8p11.22 |
| Location_base_pair | Starts at 38854505 and ends at 38962779 bp from pter ( according to hg19-Feb_2009) [Mapping] |
| Local_order | TACC1 - PLEKHA2 - HTRA4 - TM2D2 - ADAM9 - ADAM32 - ADAM5p - ADAM3A - ADAM18 - ADAM2 TACC1; 8P11; Transforming, acidic coiled-coil containing protein 1 PLEKHA2; 8P11.23; Pleckstrin homology domain containing, family A member 2 HTRA4; 8P11.23; HtrA serine peptidase 4 TM2D2; 8P11.23; TM2 domain containing 2 ADAM9; 8P11.23; a disintegrin and metalloproteinase domain 9 ADAM32; 8p11.23; ADAM metalloproteinase domain 32 ADAM5P; 8p11.23; ADAM metallopeptidase domain 5 pseudogene ADAM3A; 8p11.23; ADAM metallopeptidase domain 3A (Cyritestin 1) ADAM18; 8p11.22; ADAM metallopeptidase domain 18 ADAM2; 8p11.22; ADAM metallopeptidase domain 2. |
| Note | The ADAM9 gene, a member of the ADAM super-family have metalloprotease, integrin binding and cell adhesion capacities. It shown the metalloprotease domain cleaves insulin beta-chain, TNF-alpha, gelatin, beta-casein, fibronectin, as well as shedding of EGF, HB-EGF and FGFR2IIIB. The integrin domain mediates cellular adhesion through alpha6beta1 and alphavbeta5 integrins. The cytoplasmic tail of ADAM9 has been reported to interact with endophilin 1 (SH3GL2), SH3PX1 and mitotic arrest deficient 2beta. ADAM9 has implicated mediated by stress, such as oxidation during inflammation and cancer progression. |
| DNA/RNA |
| Note | The ADAM9 gene transcript 2 isoforms of mRNA with altered splicing results the lost of exon 18 in the second isoform of ADAM9 mRNA and early stop codon. |
 | |
| ADAM9 gene is located on chromosome 8p11.23 spread out on 108,276 deoxynucleotides contained 22 exons. The coding sequence of ADAM9 is 2460 nucleotides. Two isoforms reported, isoform 1 of ADAM9 carried full-length membrane bond ADAM9 and isoform 2 carried soluble form of ADAM9 (sADAM9). The sADAM9 is due to alternative splicing in which lost of exon 18 and results in early stop translation in exon 19. | |
| Description | ADAM9 gene extends 108,276 base pairs with 22 exons which gives rise to 2 different ADAM9 transcripts with differential splicing. The mRNA of ADAM9 isoform 1 is 4111 base pair and isoform 2 is 4005. ADAM9 isoform 2 lacks exon 18 of isoform 1 in the coding region, which results in a frameshift and an early stop codon. The isoform 2 lacks the c-terminal transmembrane and cytoplasmic domains and is a secreted form. |
| Transcription | Isoform 1 mRNA of ADAM9 (NM_003816) has a size of 4111 bp, isoform 2 mRNA (NM_001005845) has a size of 4005 bp. ADAM9 mRNA is equally expressed in many tissue. Among cancer progression, ADAM9 mRNA is relatively highly expressed in prostate cancer and breast cancer. However, little is known of differential expression between different isoform of ADAM9. |
| Pseudogene | No pseudogene has reported for ADAM9. |
| Protein |
| Note | Two different isoform of ADAM9 was reported, the full length and soluble form of ADAM9. Recent report suggests promoter polymorphisms regulated ADAM9 transcription that play a protective role against Alzheimer's disease. | ||||||||||||||
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| Two isoforms of ADAM9 with their specific function. Soluble form of ADAM9 has function to active APP either on the same cell or neighbor cell. | |||||||||||||||
| Description | The predicted molecular mass of ADAM9 is about 84 KDa. ADAM9 contained coding sequence of 2460 nucleotides which encoding amino acid of 819 residues. The full length of active ADAM9 contained several functional regions including metalloproteinase, disintegrin, cystein rich, EGF-like, transmembrane and cytoplasmic domains. The pro-domain of ADAM9 was removed by furin-type convertase during ADAM9 translocated onto membrane and become active form. Recent reports indicated soluble form of ADAM9 cloned from human cDNA library that showed increased of cancer invasion in malignant progression. | ||||||||||||||
| Expression | ADAM9 is ubiquitously expressed. SAGE analyses of ADAM9 expression demonstrated that ADAM9 is expressed in the bone marrow, lymph node, brain, retina, heart, skin, muscle, lung, prostate, breast and placenta. Increased expression of ADAM9 was reported in several cancers, including gastric, breast, prostate, colon, and pancreatic cancers. Splicing alteration and lost of exon 18 of ADAM9 causes lost of transmembrane domain and early stop in soluble form of ADAM9. | ||||||||||||||
| Localisation | Full length has N-terminal signal peptide and a single hydrophobic region predicted to be transmembrane domain. Hence, the full length of ADAM9 is localized to the plasma membrane. Soluble ADAM9 lack the transmembrane domain and cytoplasmic domain and to be released out of cell. | ||||||||||||||
| Function | 1. Ectodomain shedding: Metalloproteinase domain of ADAM9 is zinc dependent. Metalloproteinase has been showed to involve ectodomain shedding (see table below). One such protein is the heparin-binding EGF-like growth factor (HB-EGF) and amyloid precursor protein (APP). TABLE : Substrate and Peptide Sequence Cleaved
2. Matrix Degradation: purified metalloproteinase domain of ADAM9 showed the ability to digest fibronectin, gelatin and beta-casein. Secreted form of ADAM9 showed the ability to digest laminin and promote cancer invasion. 3. Cell contact: ADAM9 specifically bind to integrin alpha6beta1, a laminin receptor, via disintegrin region of ADAM9 through non-RGD mechanism. ADAM9 also have been implicated in binding of avbeta5 in divalent cation dependent condition, suggests ADAM9 can function as adhesion molecule for cell-cell and cell-martrix interaction. Secreted form of ADAM9 binds directly to alpha6beta4 and alpha2beta1 integrin and ability to cleave laminin and promote cancer progression. 4. Cysteine-Rich domain: The ADAM Cysteine-rich domain is not found in other organisms, such as virus, archaeal, bacterial or plant. The function of cysteine-rich domain might involved in complement the binding ability of disintegrin-mediated interactions. | ||||||||||||||
| Homology | The table below gives homology between the human ADAM9 and others organisms. | ||||||||||||||
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| Mutations |
| Note | Single nucleotide polymorphosim analyses of chromosome 8 demonstrated about 356 SNP in the chromosome 8p11.23. Most of them are located in intron of ADAM9. No mutation was reported in ADAM9 coding sequence. Recent evidence suggests promoter polymorphisms that may upregulate ADAM9 transcription, such as -1314C has higher of transcription activities. |
 | |
| ADAM9 gene promoter region contained 4 polymorphisms: -542C/T, -600A/C, -963A/G and -1314T/C. 1314C showed higher ADAM9 transcription compared to 1314T. | |
| Implicated in |
| Entity | Prostate cancer |
| Note | ADAM9 has been implicated in prostate cancer progression and the production of reactive oxygen species. Large cohort of clinic evaluation demonstrated ADAM9 is upregulated in prostate cancer in both mRNA and protein level. ADAM9 protein expression can be upregulated by androgen in AR-positive but not in AR-negative prostate cancer cells that is through downstream ROS as mediator to induce ADAM9 expression. ADAM9 protein expression is associated with shortened PSA-relapse-free survival in clinic evaluation. |
| Entity | Pancreatic cancer |
| Note | Pancreatic ductal adenocarcinomas showing increased of ADAM9 expression in microarray analyses and clinic evaluation that correlated with poor tumor differentiation and shorter overall survival rate. |
| Entity | Breast cancer |
| Note | ADAM9 expression is 24% positive in normal breast tissue and 66% positive in breast carcinomas. Western blot studies demonstrated multiform of ADAM9 were expressed in breast carcinoma. In addition, recent study demonstrated copy number abnormalities occurred in ADAM9 gene. |
| Entity | Lung cancer |
| Note | The increased of ADAM9 expression in lung cancer enhanced cell adhesion and invasion of non-small cell lung cancer through change adhesion properties and sensitivity to growth factors, and increase its capacity of brain metastasis. |
| Entity | Renal cell carcinoma |
| Note | ADAM9 was implicated increased expression in renal cell carcinoma and associated with tumor progression. It also showed higher of ADAM9 expression is associated with shorten patient survival rate. |
| Entity | Alzheimer's disease |
| Note | The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein processed via either the non-amyloidogenic or amyloidogenic pathways. In the non-amyloidogenic pathway, alpha-secretase cleaves APP within the Abeta peptide region releasing a large soluble fragment sAPPalpha that has neuroprotective properties. In the amyloidogenic pathway, beta-secretase and gamma-secretase sequentially cleave APP to generate the intact Abeta peptide, which is neurotoxic. In ADAM9 expression analyses showed increase in production of sAPPalpha upon phorbol ester treatment of cell that co-express of ADAM9 and APP. ADAM9 did not cleave at the Lys16-Leu17 bone but at the His14-Gln15 bone in the Abeta domain of APP cleave site. Hence, ADAM9 might play role in protective against sporadic Alzheimer's disease. |
| External links |
| Bibliography |
| A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. |
| Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, Miyado K, Tamai Y, Kurisaki T, Sehara-Fujisawa A, Ohno S, Mekada E. |
| EMBO J. 1998 Dec 15;17(24):7260-72. |
| PMID 9857183 |
| Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta. |
| Nelson KK, Schlondorff J, Blobel CP. |
| Biochem J. 1999 Nov 1;343 Pt 3:673-80. |
| PMID 10527948 |
| Intracellular processing of metalloprotease disintegrin ADAM12. |
| Cao Y, Kang Q, Zhao Z, Zolkiewska A. |
| J Biol Chem. 2002 Jul 19;277(29):26403-11. Epub 2002 May 8. |
| PMID 12000744 |
| A secreted form of human ADAM9 has an alpha-secretase activity for APP. |
| Hotoda N, Koike H, Sasagawa N, Ishiura S. |
| Biochem Biophys Res Commun. 2002 May 3;293(2):800-5. |
| PMID 12054541 |
| Gene expression profiles of microdissected ductal adenocarcinoma. |
| Grutzmann R, Foerder M, Alldinger I, Staub E, Brummendorf T, Ropcke S, Li X, Kristiansen G, Jesnowski R, Sipos B, Lohr M, Luttges J, Ockert D, Kloppel G, Saeger HD, Pilarsky C. |
| Virchows Arch. 2003 Oct;443(4):508-17. Epub 2003 Aug 27. |
| PMID 12942322 |
| Oxidative and osmotic stress signaling in tumor cells is mediated by ADAM proteases and heparin-binding epidermal growth factor. |
| Fischer OM, Hart S, Gschwind A, Prenzel N, Ullrich A. |
| Mol Cell Biol. 2004 Jun;24(12):5172-83. |
| PMID 15169883 |
| ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma. |
| Grutzmann R, Luttges J, Sipos B, Ammerpohl O, Dobrowolski F, Alldinger I, Kersting S, Ockert D, Koch R, Kalthoff H, Schackert HK, Saeger HD, Kloppel G, Pilarsky C. |
| Br J Cancer. 2004 Mar 8;90(5):1053-8. |
| PMID 14997207 |
| Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. |
| Shintani Y, Higashiyama S, Ohta M, Hirabayashi H, Yamamoto S, Yoshimasu T, Matsuda H, Matsuura N. |
| Cancer Res. 2004 Jun 15;64(12):4190-6. |
| PMID 15205330 |
| Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer. |
| Alldinger I, Dittert D, Peiper M, Fusco A, Chiappetta G, Staub E, Lohr M, Jesnowski R, Baretton G, Ockert D, Saeger HD, Grutzmann R, Pilarsky C. |
| Pancreatology. 2005;5(4-5):370-9. Epub 2005 Jun 23. |
| PMID 1598344 |
| Developmental expression of metalloproteases ADAM 9, 10, and 17 becomes restricted to divergent pancreatic compartments. |
| Asayesh A, Alanentalo T, Khoo NK, Ahlgren U. |
| Dev Dyn. 2005 Apr;232(4):1105-14. |
| PMID 15739225 |
| The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer. |
| Carl-McGrath S, Lendeckel U, Ebert M, Roessner A, Rocken C. |
| Int J Oncol. 2005 Jan;26(1):17-24. |
| PMID 15586220 |
| A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. |
| Mazzocca A, Coppari R, De Franco R, Cho JY, Libermann TA, Pinzani M, Toker A. |
| Cancer Res. 2005 Jun 1;65(11):4728-38. |
| PMID 15930291 |
| Critical function for ADAM9 in mouse prostate cancer. |
| Peduto L, Reuter VE, Shaffer DR, Scher HI, Blobel CP. |
| Cancer Res. 2005 Oct 15;65(20):9312-9. |
| PMID 16230393 |
| Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. |
| Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T, Chen F, Feiler H, Tokuyasu T, Kingsley C, Dairkee S, Meng Z, Chew K, Pinkel D, Jain A, Ljung BM, Esserman L, Albertson DG, Waldman FM, Gray JW. |
| Cancer Cell. 2006 Dec;10(6):529-41. |
| PMID 17157792 |
| Overexpression of ADAM9 enhances growth factor-mediated recycling of E-cadherin in human colon cancer cell line HT29 cells. |
| Hirao T, Nanba D, Tanaka M, Ishiguro H, Kinugasa Y, Doki Y, Yano M, Matsuura N, Monden M, Higashiyama S. |
| Exp Cell Res. 2006 Feb 1;312(3):331-9. Epub 2005 Dec 5. |
| PMID 16336960 |
| Oxidative stress induces ADAM9 protein expression in human prostate cancer cells. |
| Sung SY, Kubo H, Shigemura K, Arnold RS, Logani S, Wang R, Konaka H, Nakagawa M, Mousses S, Amin M, Anderson C, Johnstone P, Petros JA, Marshall FF, Zhau HE, Chung LW. |
| Cancer Res. 2006 Oct 1;66(19):9519-26. |
| PMID 17018608 |
| ADAMs in cancer cell proliferation and progression. |
| Mochizuki S, Okada Y. |
| Cancer Sci. 2007 May;98(5):621-8. Epub 2007 Mar 9. |
| PMID 17355265 |
| Reactive oxygen species mediate androgen receptor- and serum starvation-elicited downstream signaling of ADAM9 expression in human prostate cancer cells. |
| Shigemura K, Sung SY, Kubo H, Arnold RS, Fujisawa M, Gotoh A, Zhau HE, Chung LW. |
| Prostate. 2007 May 15;67(7):722-31. |
| PMID 17342749 |
| ADAM9 expression is a significant and independent prognostic marker of PSA relapse in prostate cancer. |
| Fritzsche FR, Jung M, Tolle A, Wild P, Hartmann A, Wassermann K, Rabien A, Lein M, Dietel M, Pilarsky C, Calvano D, Grutzmann R, Jung K, Kristiansen G. |
| Eur Urol. 2008 Nov;54(5):1097-106. Epub 2007 Nov 26. |
| PMID 18061337 |
| ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression. |
| Fritzsche FR, Wassermann K, Jung M, Tolle A, Kristiansen I, Lein M, Johannsen M, Dietel M, Jung K, Kristiansen G. |
| BMC Cancer. 2008 Jun 26;8:179. |
| PMID 18582378 |
| Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis. |
| Boelens MC, Kok K, van der Vlies P, van der Vries G, Sietsma H, Timens W, Postma DS, Groen HJ, van den Berg A. |
| Lung Cancer. 2009 Mar 24. |
| PMID 19324446 |
| Expression of ADAMs ("a disintegrin and metalloprotease") in the human lung. |
| Dijkstra A, Postma DS, Noordhoek JA, Lodewijk ME, Kauffman HF, Ten Hacken NH, Timens W. |
| Virchows Arch. 2009 Apr;454(4):441-9. Epub 2009 Mar 3. |
| PMID 19255780 |
| ADAM9 is involved in pathological retinal neovascularization. |
| Guaiquil V, Swendeman S, Yoshida T, Chavala S, Campochiaro PA, Blobel CP. |
| Mol Cell Biol. 2009 May;29(10):2694-703. Epub 2009 Mar 9. |
| PMID 19273593 |
| EGFR and ADAMs cooperate to regulate shedding and endocytic trafficking of the desmosomal cadherin desmoglein 2. |
| Klessner JL, Desai BV, Amargo EV, Getsios S, Green KJ. |
| Mol Biol Cell. 2009 Jan;20(1):328-37. Epub 2008 Nov 5. |
| PMID 18987342 |
| Up-regulated expression of ADAM17 in gastrointestinal stromal tumors: coexpression with EGFR and EGFR ligands. |
| Nakagawa M, Nabeshima K, Asano S, Hamasaki M, Uesugi N, Tani H, Yamashita Y, Iwasaki H. |
| Cancer Sci. 2009 Feb 27. |
| PMID 19298600 |
| UV-induced EGFR signal transactivation is dependent on proligand shedding by activated metalloproteases in skin cancer cell lines. |
| Singh B, Schneider M, Knyazev P, Ullrich A. |
| Int J Cancer. 2009 Feb 1;124(3):531-9. |
| PMID 19003995 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 04-2009 | Shian-Ying Sung |
| Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan |
| Citation |
| This paper should be referenced as such : |
| Sung SY . ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)). Atlas Genet Cytogenet Oncol Haematol. April 2009 . |
| URL : http://AtlasGeneticsOncology.org/Genes/ADAM9ID573ch8p11.html |
The various updated versions of this paper are referenced and archived by INIST as such : |
| http://documents.irevues.inist.fr/bitstream/2042/44708/1/04-2009-ADAM9ID573ch8p11.pdf [ Bibliographic record ] |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Feb 26 10:09:59 CET 2014 |
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